Abstract Rapid progress in the discovery of disease biomarkers commands the development of high-performance detection systems that can achieve the requisite levels of speed, sensitivity and accuracy. With extraordinary sensitivity and dynamic range, solid state nanopore (ssNP)-based electrical counting methods are the leading candidates to meet this need. In processing one molecule at a time however, ssNPs must overcome a major challenge in throughput before they can be used to analyze clinical samples. This project will develop a novel dual membrane device (NPN/ ssNP) to address two critical issues limiting nanopore performance: short lifetimes and diffusion-limited capture rates. The enabling feature of the device is the addition of a highly porous silicon nanomembrane (NPN) immediately upstream of the ssNP. The membrane serves as a filter to prevent clogging and enables microfluidic delivery of biomarkers. When combined with parallelization and biomarker amplification, the dual membrane device should yield a 106 improvement in throughput, enabling ssNP technology to detect biomarkers at sub-picomolar clinical concentrations in practical time periods (minutes). The project will establish proof-of- principle in work organized under three Aims. Aim 1 thoroughly characterize the new device and produce an optimum configuration for DNA capture. Aim 2 will elucidate the benefits of microfluidic delivery of sample. Finally, Aim 3 will apply the lessons of Aims 1 and 2 to maximum benefit and demonstrate the detection of fM concentrations of biomarker in under 10 minutes from 10 ul of blood plasma.